Anjum Iram, Aslam Komal, Jamil Tabitha Mavish, John Munawar, Baig Shahid Mahmood, Eiberg Hans, Hansen Lars, Tommerup Niels
Department of Biotechnology, Kinnaird College of Women, Lahore, Pakistan.
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology & Genetic Engineering (NIBGE) College, PIEAS, Faisalabad, Pakistan.
Mol Biol Rep. 2025 Oct 25;53(1):11. doi: 10.1007/s11033-025-11109-7.
Primary congenital glaucoma (PCG) is a rare genetic disorder affecting the ocular drainage system, accounting for only 0.01-0.04% blindness related cases. However, its prevalence varies significantly in ethnicities, being higher in populations that practice consanguinity, such as Pakistan where approximately 70% of marriages are consanguineous. This study aimed to investigate the genetic cause of PCG in a large Pakistani family with autosomal recessive inheritance.
A large multigenerational family having multiple consanguineous marriages resulting in fifteen affected individuals was recruited for the current study. All relevant clinical information was collected and venous blood drawn for further genetic analysis. The family was subjected to direct sequencing of CYP1B1 which is the most plausible candidate of PCG. The resulting candidate variant was further confirmed using BanII restriction enzyme analysis.
The sequence analysis revealed a novel indel (c.862delinsCC) in exon 2 of the CYP1B1 gene, resulting in a frameshift mutation (p.Ala288Profs*39) thereby creating a premature stop codon 39 amino acids downstream. BanII restriction enzyme analysis further confirmed this putative null mutation co-segregating with the disease trait in all the family members of the pedigree.
The novel indel, putative null mutation causes PCG related disease phenotypes. This genetic variant has a high penetrance but shows variable expressivity among the affected members of the family. This putative null mutation enhances the mutation spectrum of CYP1B1 globally and from Pakistan in particular.
原发性先天性青光眼（PCG）是一种罕见的影响眼部引流系统的遗传性疾病，仅占失明相关病例的0.01 - 0.04%。然而，其患病率在不同种族中差异显著，在近亲结婚的人群中更高，例如在巴基斯坦，约70%的婚姻为近亲婚姻。本研究旨在调查一个具有常染色体隐性遗传的大型巴基斯坦家族中PCG的遗传病因。
本研究招募了一个有多代近亲婚姻、导致15名患者的大型家族。收集了所有相关临床信息，并采集静脉血用于进一步的基因分析。对该家族进行了CYP1B1的直接测序，CYP1B1是PCG最有可能的候选基因。使用BanII限制性内切酶分析进一步确认所得的候选变异。
序列分析显示CYP1B1基因外显子2中有一个新的插入缺失（c.862delinsCC），导致移码突变（p.Ala288Profs*39），从而在下游39个氨基酸处产生一个提前终止密码子。BanII限制性内切酶分析进一步证实了这个推定的无效突变与家系中所有家族成员的疾病性状共分离。
这种新的插入缺失，即推定的无效突变导致了与PCG相关的疾病表型。这种基因变异具有高外显率，但在家族中受影响的成员中表现出可变的表达度。这个推定的无效突变增加了全球尤其是来自巴基斯坦的CYP1B1突变谱。
